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Novel Cyclic Compound Having Pyrimidinylalkylthio Group

a technology of pyrimidinylalkylthio group and cyclic compound, which is applied in the direction of biocide, drug composition, cardiovascular disorder, etc., can solve the problem of no description of cyclic compound having a pyrimidinylalkylthio group, and achieve excellent antiangiogenic

Inactive Publication Date: 2009-11-26
SANTEN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]The present invention provides a novel cyclic compound having a pyrimidinylalkylthio group or a salt thereof useful as a pharmaceutical. The novel cyclic compound according to the present invention has an excellent antiangiogenic effect, and is useful as a therapeutic agent for a disease associated with angiogenesis, for example, cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoid choroidal angiopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis or the like.

Problems solved by technology

However, there is no description on cyclic compounds having a pyrimidinylalkylthio group in these Patent publications.

Method used

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  • Novel Cyclic Compound Having Pyrimidinylalkylthio Group
  • Novel Cyclic Compound Having Pyrimidinylalkylthio Group
  • Novel Cyclic Compound Having Pyrimidinylalkylthio Group

Examples

Experimental program
Comparison scheme
Effect test

production example

Reference Example 1

2-Dimethylamino-4-trifluoromethylpyrimidine (Reference Compound No. 1-1)

[0148]

[0149]2-Chloro-4-trifluoromethylpyrimidine (600 μL, 5.0 mmol) was dissolved with 2.0M dimethylamine in methanol (10 mL), and stirred for 2 hours in a sealed tube at 60° C. The reaction mixture was diluted with ethyl acetate (50 mL), and the whole was washed with water (50 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 640 mg of the title Reference Compound as a colorless oil (Yield: 0.67%).

[0150]1H-NMR (400 MHz, CDCl3)

[0151]δ 3.22 (s, 6H), 6.72 (d, J=4.9 Hz, 1H), 8.48 (d, J=4.9 Hz, 1H)

reference example 2

2-Dimethylamino-4-methoxycarbonylpyrimidine (Reference Compound No. 2-1)

[0152]

[0153]2-Dimethylamino-4-trifluoromethylpyrimidine (320 mg, 1.7 mmol, Reference Compound No. 1-1) and sodium hydroxide (670 mg, 17 mmol) were suspended in a mixed solvent of methanol (5.0 mL) and water (5.0 mL), and then the mixture was stirred while radiated with microwave for 2 and a half hours at 160° C. in a sealed tube. The reaction mixture was diluted with ethyl acetate (30 mL), and extracted with water (30 mL), and then extracted with saturated aqueous sodium hydrogencarbonate solution (30 mL). The extracted aqueous layer was adjusted to pH7 with 6M hydrochloric acid, and was concentrated under reduced pressure. The remaining residue was suspended in N,N-dimethylformamide (5.0 mL), then sodium hydrogencarbonate solution (1.3 g, 14 mmol) and methyl iodide (0.87 mL, 17 mmol) were added thereto, and the whole was stirred for 23 hours at room temperature. The reaction mixture was diluted with ethyl aceta...

reference example 3

2-Amino-4-methoxycarbonylpyrimidine (Reference Compound No. 3-1)

[0156]

[0157]Triethylamine (29 mL, 210 mmol) was added to a suspension of methyl 4-butoxy-2-oxo-3-butenate (37 g, 200 mmol, JP-A-2003-89690) and guanidine hydrochloride (23 g, 240 mmol) in propionitrile (50 mL), and the mixture was stirred for 4 hours at 100° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 18 g as the mixture of the title Reference Compound and the butyl ester form of the title Reference compound as a gray-white solid (Yield: 60%).

[0158]1H-NMR (500 MHz, DMSO-d6)

[0159]δ 3.85 (s, 3H), 6.99-7.06 (m, 3H), 8.48 (d, J=4.8 Hz, 1H)

[0160]As described below, Reference Compounds Nos. 3-2 to 3-4 were obtained following the method similar to that of Reference Compound No. 3-1, using the corresponding compounds selected from compounds which are on the market or compounds which are commonly known.

4-Methoxycarbonyl-2-methylthiopyri...

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Abstract

The present invention has its object to study synthesis of novel cyclic compounds having a pyrimidinylalkylthio group and to find pharmacological actions of the compounds. According to the present invention, a compound represented by the formula (1) or a salt thereof is provided.In the formula, the ring X represents:R1 and R2 independently represent a hydrogen atom, an alkyl group, an aryl group, an aromatic heterocyclic group or the like; R3 represents a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, an alkyl group, an aryl group, an amino group, an alkylamino group or the like; A1 represents a sulfur atom or the like; and A2 represents an alkylene group.

Description

TECHNICAL FIELD[0001]The present invention relates to a novel cyclic compound having a pyrimidinylalkylthio group or a salt thereof useful as a pharmaceutical. Such a compound is useful as a therapeutic agent for a disease associated with angiogenesis, particularly as a therapeutic agent for cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoid choroidal angiopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis or the like.BACKGROUND ART[0002]Angiogenesis is a phenomenon in which a new vascular network is formed from an existing blood vessel and is observed mainly in a microvessel. Angiogenesis is originally a physiological phenomenon and is essential for blood vessel formation in fetal life, but it is usually observed only at a limited site such as endometrium or follicle or at a limited period such as a wound healing process in adults. However, pathological angiogenesis is ob...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5377C07D239/02C07D413/02A61K31/506A61P35/00
CPCC07D239/42C07D409/12C07D401/14C07D401/12A61P9/00A61P9/10A61P17/06A61P19/02A61P27/02A61P29/00A61P35/00
Inventor TAJIMA, HISASHIHONDA, TAKAHIROKAWASHIMA, KENJIOKAMOTO, KAZUYOSHIYAMAMOTO, MINORU
Owner SANTEN PHARMA CO LTD
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